Chronic lymphocytic leukemia (CLL) patients have a disease related innate, humoral, and cellular immune deficiency leading to infections and secondary cancers. While therapy of CLL has improved, these treatments are immunosuppressive, not curative and contribute to worsening infectious morbidity. To date, only allogeneic stem cell transplant has demonstrated the ability to produce sustained remissions in CLL, but this therapy is associated with significant morbidity and mortality. Transplant strategies are not ideal relative to treatment-related morbidity and mortality, but they do illustrate the power of an active immune response against drug-resistant CLL. Developing agents that enhance autologous innate, cellular and humoral immune function to eliminate genetic high-risk CLL would constitute a major advance in CLL therapy. One such therapy is lenalidomide, an agent that activates T cells and NK cells to be directly cytotoxic to cancer cells. To date, lenalidomide has demonstrated clinical activity in myelodysplastic syndrome, multiple myeloma, and B-cell malignancies including CLL. Lenalidomide produces a disease specific significant toxicity of acute tumor flare that has raised concern about the use in this disease. We have demonstrated that lenalidomide tumor flare may occur as a consequence of B-cell activation via increased NF-KB DNA binding that is dependent on activation of the PI3-kinase pathway and inhibition of the protein phosphatase PP2A. As a consequence of B cell activation, several genes are up-regulated that potentially antagonize the efficacy of this agent in vivo and contributes to tumor flare characteristics. This proposal utilizes a well integrated laboratory and clinical team focused on translational studies of lenalidomide in CLL. Our specific aims include: 1)to determine the mechanism(s) by which lenalidomide promotes activation of CLL cells;2) to determine if lenalidomide-mediated CLL cell activation promotes tumor flare and classic drug resistance concurrent with development of combination strategies to enhance the safety and efficacy of this therapy; and 3) to perform a phase l/ll clinical trial of lenalidomide in patients with active relapsed CLL (Stratum 2A) and those receiving therapy for minimal residual disease following cytoreductive therapy (Stratum 2B) with detailed correlative studies that are derived from the investigations in aims 1 and 2. Successful pursuit of these aims will transition lenalidomide or a derivative of this to an influential position in CLL therapy contributing to an approach that affords durable, well-tolerated remission in the majority of patients treated. RELEVANCE (See instructions): CLL is the most common type of adult leukemia and is incurable with current therapies. Lenalidomide has demonstrated clinical activity in resistant CLL but also can result in life threatening toxicity. This proposal extends from extensive preliminary data and proposes both laboratory and clinical studies to optimize lenalidomide use in CLL. The findings of these studies are quite relevant to improving future treatment strategies of CLL and also to increasing patient safety.